Macrophages are involved in every cardiovascular disease and are an attractive therapeutic target. Macrophage activation is complex and can be either beneficial or deleterious, depending upon its mode of action, its timing, and its duration. An important macrophage characteristic is its plasticity, which enables it to switch from one subset to another. Macrophages, which regulate healing and repair after myocardial infarction, have become a major target for both treatment and diagnosis (theranostic). The aim of the present review is to describe the recent discoveries related to targeting and modulating of macrophage function to improve infarct repair. We will briefly review macrophage polarization, plasticity, heterogeneity, their role in infarct repair, regeneration, and cross talk with mesenchymal cells. Particularly, we will focus on the potential of macrophage targeting in situ by liposomes. The ability to modulate macrophage function could delineate pathways to reactivate the endogenous programs of myocardial regeneration. This will eventually lead to development of small molecules or biologics to enhance the endogenous programs of regeneration and repair.

The bacterial N-3-oxo-dodecanoyl-L-homoserine lactone (C12) has critical roles in both inter-bacterial communication and inter-kingdom signaling. The ability of C12 to down-regulate production of the key pro-inflammatory cytokine tumor necrosis factor α (TNFα) in stimulated macrophages was suggested to contribute to the establishment of chronic infections by opportunistic Gram-negative bacteria, such as Pseudomonas aeruginosa. We show that in contrast to TNFα suppression, C12 amplifies production of the major anti-inflammatory cytokine interleukin-10 (IL-10) in lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophages as well as peritoneal macrophages. Furthermore, C12 increases IL-10 mRNA level and IL-10 promoter reporter activity in LPS-stimulated RAW264.7 macrophages, indicating that C12 modulates IL-10 expression at the transcriptional level. Finally, C12 substantially potentiated LPS-stimulated NFκB DNA-binding level, and prolonged p38 MAP kinase phosphorylation in the RAW264.7 macrophages, suggesting that increased transcriptional activity of NFκB and/or p38-activated transcription factors serves to up-regulate IL-10 production in macrophages exposed to both LPS and C12. These findings reveal another part of the complex array of host transitions through which opportunistic bacteria down-regulate immune responses in order to flourish and establish a chronic infection.

Expression of the key anti-inflammatory cytokine IL-10 in lipopolysaccharide (LPS)-stimulated macrophages is mediated by a delayed autocrine/paracrine loop of type I interferons (IFN) to ensure timely attenuation of inflammation. We have previously shown that cAMP synergizes with early IL-10 expression by LPS, but is unable to amplify the late type I IFN-dependent activity. We now examined the mechanism of this synergistic transcription in mouse macrophages at the promoter level, and explored the crosstalk between type I IFN signaling and cAMP, using the β-adrenergic receptor agonist, isoproterenol, as a cAMP inducer. We show that silencing of the type I IFN receptor enables isoproterenol to synergize with LPS also at the late phase, implying that autocrine type I IFN activity hinders synergistic augmentation of LPS-stimulated IL-10 expression by cAMP at the late phase. Furthermore, IL-10 expression in LPS-stimulated macrophages is exclusively stimulated by either IFNα or isoproterenol. We identified a set of two proximate and inter-dependent cAMP response element (CRE) sites that cooperatively regulate early IL-10 transcription in response to isoproterenol-stimulated CREB and that further synergize with a constitutive Sp1 site. At the late phase, up-regulation of Sp1 activity by LPS-stimulated type I IFN is correlated with loss of function of the CRE sites, suggesting a mechanism for the loss of synergism when LPS-stimulated macrophages switch to type I IFN-dependent IL-10 expression. This report delineates the molecular mechanism of cAMP-accelerated IL-10 transcription in LPS-stimulated murine macrophages that can limit inflammation at its onset.

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Interleukin-10 (IL-10) is a key anti-inflammatory cytokine, secreted by macrophages and other immune cells to attenuate inflammation. Autocrine type I interferons (IFNs) largely mediate the delayed expression of IL-10 by LPS-stimulated macrophages. We have previously shown that IL-10 is synergistically expressed in macrophages following a costimulus of a TLR agonist and cAMP. We now show that the cAMP pathway directly upregulates IL-10 transcription and plays an important permissive and synergistic role in early, but not late, LPS-stimulated IL-10 mRNA and protein expression in mouse macrophages and in a mouse septic shock model. Our results suggest that the loss of synergism is not due to desensitization of the cAMP inducing signal, and it is not mediated by a positive crosstalk between the cAMP and type I IFN pathways. First, cAMP elevation in LPS-treated cells decreased the secretion of type I IFN. Second, autocrine/paracrine type I IFNs induce IL-10 promoter reporter activity only additively, but not synergistically, with the cAMP pathway. IL-10 promoter reporter activity was synergistically induced by cAMP elevation in macrophages stimulated by an agonist of either TLR4, TLR2/6, or TLR7, receptors which signal via MyD88, but not by an agonist of TLR3 which signals independently of MyD88. Moreover, MyD88 knockout largely reduced the synergistic IL-10 expression, indicating that MyD88 is required for the synergism displayed by LPS with cAMP. This report delineates the temporal regulation of early cAMP-accelerated vs. late type I IFN-dependent IL-10 transcription in LPS-stimulated murine macrophages that can limit inflammation at its onset.

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